Thyrotropin releasing hormone (TRH) maintains thyroid function by stimulating pituitary thyrotropin (TSH) secretion. TRH also stimulates prolactin (Prl) secretion. Recently TRH immunoreactivity (IR) has been detected in extrahypothalamic brain, the pancreatic islets, and the bowel. Moreover, TRH has metabolic effects on these tissues. TRH opposes some of the actions of alcohol on the brain and may modulate glucagon secretion. The pharmocologic effects of synthetic TRH have been studied in many organs. However, there is a paucity of information on the actual sites of TRH biosynthesis, the rates of TRH biosynthesis at its production sites, and the rates of TRH delivery to its sites of action (TRH economy). Unfortunately, the study of TRH economy is a formidable problem because endogenous TRH is difficult to measure and the organ source(s) for any TRH measured in plasma, urine, or other biological fluids need to be identified. However, the nature of certain TRH precursors of metabolites detected in plasma and urine might identify, respectively, their site of synthesis or site of action. Therefore, information regarding TRH economy could be generated by developing our understanding of the nature, metabolic actions, and metabolism of TRH precursors and metabolites. The research objectives of this proposal are to develop this information with respect to three of these substances. They are, (1) "proTRH", a high molecular weight compound in neonatal rat blood possessing TRH IR, (2) TRH-OH, the deamidated analogue of TRH and its putative metabolite, and (3) His-Pro diketopiperazine, a putative metabolite of TRH which possesses intrinsic bio-activity. Distrubances in TRH economy might be associated with diseases of the pituitary (TSH and Prl secretory states), brain, pancreatic islets (Diabetes Mellitus), and bowel. Fulfillment of the research objectives of this proposal may be useful in improving our understanding of these disease states.